To evaluate to what extent indicators of placenta insufficiency are associated with low concentrations of insulin-like growth factor 1 (IGF-1) and IGF-1-binding protein-1 (IGFBP-1) in neonatal blood, and to what extent the concentrations of these growth factors are associated with concentrations of proteins with inflammatory, neurotrophic, or angiogenic properties.
Using multiplex immunoassays, we measured the concentrations of IGF-1 and IGFBP-1, as well as 25 other proteins in blood spots collected weekly from ≥ 880 infants born before the 28th week of gestation, and sought correlates of concentrations in the top and bottom quartiles for gestational age and day the specimen was collected.
Medically indicated delivery and severe fetal growth restriction (sFGR) were associated with low concentrations of IGF-1 on the first postnatal day and with high concentrations of IGFBP-1 on almost all days. Elevated concentrations of IGF-1 and IGFBP-1 were accompanied by elevated concentrations of many other proteins with inflammatory, neurotrophic, or angiogenic properties.
Disorders associated with impaired placenta implantation and sFGR appear to account for a relative paucity of IGF-1 on the first postnatal day. Elevated concentrations of IGF-1 and especially IGFBP-1 were associated with same-day elevated concentrations of inflammatory, neurotrophic, and angiogenic proteins.
Socioeconomic status and early blood concentrations of inflammation-related and neurotrophic proteins among extremely preterm newborns.
Leviton, A., Allred, E. N., Dammann, O., Joseph, R. M., Fichorova, R. N., O’Shea, T. M., Kuban, K. C.
The main objective of this study was to evaluate the relationship between mother’s socioeconomic disadvantage and blood concentrations of inflammation-related proteins among extremely preterm newborns (<28 weeks gestation), a group at heightened risk of cognitive impairment when exposed to systemic inflammation. We measured the concentrations of 27 inflammatory and neurotrophic proteins in blood specimens collected a week apart during the first postnatal month from 857 extremely preterm newborns in the United States. We classified children according to 3 indicators/correlates of socioeconomic disadvantage, mother’s eligibility for government-provided medical care insurance (Medicaid), mother’s formal education level, and mother’s IQ approximated with the Kaufman Brief Intelligence Test– 2. The risks of a top-quartile concentration of each protein on each of 5 days a week apart, on two occasions during the first two postnatal weeks, and during the next two weeks were modeled as functions of each indicator of socioeconomic disadvantage. The risks of top quartile concentrations of multiple (2–5) inflammation-related proteins on multiple days during the first two weeks were increased for each of the 3 indicators of socioeconomic disadvantage, while the risks of top quartile concentrations of selected neurotrophic proteins were reduced. Adjustment for socioeconomic disadvantage did not alter the relationships between protein concentrations and both low IQ and low working memory 10 years later. Among extremely preterm newborns, indicators of socioeconomic disadvantage are associated with modestly increased risk of systemic inflammation in postnatal blood during the first postnatal month and with a slightly reduced risk of a neurotrophic signal, but do not confound relationships between protein concentrations and outcomes.
The Journal of Maternal-Fetal & Neonatal Medicine
Antecedents and outcomes of hypothermia at admission to the neonatal intensive care unit.
Elbaum, C., Beam, K. S., Dammann, O., & Dammann, C. E. L.
To evaluate the association between morbidities preceding and following neonatal intensive care unit (NICU) admission with hypothermia.
NICU admission temperatures for 1271 infants admitted to the NICU at Tufts Medical Center (TMC) between 2012 and 2015 were compared to all Vermont Oxford Network (VON) centers in 2014. We analyzed demographic data, prevalence of hypothermia, and associations with prenatal and neonatal morbidities.
Prevalence of hypothermia at TMC was 19% compared to 25% in the VON. We found a significant association between hypothermia and maternal race, birth weight, gestational age, antenatal steroids, chorioamnionitis, mode of delivery, and Apgar scores.
Continued emphasis should be placed on avoiding neonatal hypothermia during the first hours of postnatal life.
The Journal of Neuroimmune Pharmacology
Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm.
Leviton, A., Joseph, R. M., Fichorova, R. N., Allred, E. N., Taylor, H. G., O’Shea, T. M., Dammann, O.
We evaluated the relationship between blood levels of inflammatory and neurotrophic proteins during the first postnatal month in 692 children born before the 28th week of gestation and executive function limitations among those 10-year olds who had an IQ ≥ 70. The measures of dysfunction were Z-scores ≤ -1 on the Differential Ability Scales–II working memory (WM) assessment) (N = 164), the NEPSY-II (A Developmental NEuroPSYchological Assessment-II) Inhibition-Inhibition assessment) (N = 350), the NEPSY-II Inhibition-Switching assessment) (N = 345), as well as a Z-score ≤ -1 on all three assessments (identified as the executive dysfunction composite (N = 104). Increased risks of the executive dysfunction composite associated with high concentrations of inflammatory proteins (IL-8, TNF-α, and ICAM-1) were modulated by high concentrations of neurotrophic proteins. This pattern of modulation by neurotrophins of increased risk associated with inflammation was also seen for the working memory limitation, but only with high concentrations of IL-8 and TNF-α, and the switching limitation, but only with high concentrations of ICAM-1. We infer that among children born extremely preterm, risks of executive function limitations might be explained by perinatal systemic inflammation in the absence of adequate neurotrophic capability.
The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of children born extremely preterm.
Leviton, A., Joseph, R. M., Allred, E. N., Fichorova, R. N., O’Shea, T. M., Kuban, K. K. C., & Dammann, O.
Background: Interleukin (IL)-4 and IL-10 are viewed mainly as anti-inflammatory cytokines. Yet, high concentrations have also been associated with inflammation-related diseases in newborns.
Methods: We measured the concentrations of IL-4 and IL-10, as well as IL-8 and ICAM-1 in blood specimens collected on postnatal day 21 (N = 555), day 28 (N = 521), and both days 21 and 28 (N = 449) from children born extremely preterm (EP) (<28 weeks gestation) who at age 10 years had a DAS-II IQ Z-score > −2 (which approximates a score of >70) and the following assessments, CCC-2, and CSI-4, DAS-II, NEPSY-II, OWLS-II, SCQ, and WIAT-III. Selected children also were assessed with the ADI-R and the ADOS-2. We modeled the risk of low scores or dysfunctions associated with top quartile concentrations of IL-4 and IL-10 on each day and on both days.
Results: The risks of low scores on the Animal Sorting and Arrows components of the NEPSY-II, both components of the OWLS-II, and the PseudoWord and Spelling components of the WIAT-III were heightened among children who had top quartile concentrations of IL-4 on postnatal days 21 and 28. Children who had high concentrations of IL-10 on days 21 and 28, individually and collectively, were at increased risk of low scores on the WIAT-III Spelling component. High concentrations of IL-4 on day 28 were associated with autism spectrum disorder (ASD). High concentrations of IL-10 on day 28 were also associated with a doubling of ASD risk, but this did not achieve statistical significance. Top quartile concentrations of IL-4 and IL10 on both days were not associated with increased risk of social, language, or behavioral dysfunctions.
Conclusion: Among children born EP, those who had top quartile concentrations of IL-4 and/or IL-10 on postnatal days 21 and/or 28 were more likely than their peers to have low scores on components of the NEPSY-II, OWLS-II, and WIAT-III assessments, as well as identification as having an ASD.
What is known: IL-4 and IL-10 are viewed as predominantly anti-inflammatory proteins. Less commonly, high concentrations of IL-4 and IL-10 have been associated with adverse health outcomes.
What is not known: We do not know to what extent elevated concentrations of IL-4 and IL-10 during the third and fourth postnatal weeks are associated with increased risk of neurocognitive, behavioral, language, and social dysfunctions among children born very preterm.
What this study adds: Children born very preterm who have elevated concentrations of IL-4, but not IL-10, on both postnatal days 21 and/or 28 are at increased risk of low scores on assessments of processing speed, visuospatial skills, listening comprehension, oral expression, and reading and spelling achievement.
Developmental Medicine and Child Neurology
Hypoxia–ischemia is not an antecedent of most preterm brain damage: the illusion of validity.
Gilles, F., Gressens, P., Dammann, O., Leviton, A.
Brain injury in preterm newborn infants is often attributed to hypoxia–ischemia even when neither hypoxia nor ischemia is documented, and many causative speculations are based on the same assumption. We review human and animal study contributions with their strengths and limitations, and conclude that – despite all the work done in human fetal neuropathology and developmental models in animals – the evidence remains unconvincing that hypoxemia, in the fetus or newborn infant, contributes appreciably to any encephalopathy of prematurity. Giving an inappropriate causal name to a disorder potentially limits the options for change, should our understanding of the etiologies advance. The only observationally‐based title we think appropriate is ‘encephalopathy of prematurity’. Future pathophysiological research should probably include appropriately designed epidemiology studies, highly active developmental processes, infection and other inflammatory stimuli, the immature immune system, long chain fatty acids and their transporters, and growth (neurotrophic) factors.
Early Human Development
Socioemotional dysfunctions at age 10 years in extremely preterm newborns with late-onset bacteremia.
Babata, K., Bright, H. R., Allred, E. N., Erdei, C., Kuban, K. K. C., Joseph, R. M., O’Shea, T. M., Dammann, O., Leviton, A., The ELGAN Study Investigators
Extremely preterm (EP) newborns are at increased risk for the “preterm behavioral phenotype.
We examined the communication and socioemotional characteristics associated with late-bacteremia in 10-year-olds born EP.
This prospective cohort study looked at definite late-bacteremia, suspected late-bacteremia, and no bacteremia.
Definite late-bacteremia was associated with a small, non-statistically significant increased risk of autism.
EP infants with suspected or definite late-bacteremia were at increased risk of social and communication impairments.
International Journal of Developmental Neuroscience
Neonatal systemic inflammation and the risk of low scores on measures of reading and mathematics achievement at age 10 years among children born extremely preterm.
Leviton, A., Damman, O., Allred, E. N., Joseph, R. M., Fichorova, R. N., O’Shea, T. M., Kuban, K. C. K.
Background: Difficulties with reading and math occur more commonly among children born extremely preterm than among children born at term. Reasons for this are unclear.
Methods: We measured the concentrations of 27 inflammatory-related and neurotrophic/angiogenic proteins (angio-neurotrophic proteins) in multiple blood specimens collected a week apart during the first postnatal month from 660 children born before the 28th week of gestation who at age 10 years had an IQ ≥ 70 and a Wechsler Individual Achievement Test 3rd edition (WIAT-III) assessment. We identified four groups of children, those who had a Z-score ≤ −1 on the Word Reading assessment only, on the Numerical Operations assessment only, on both of these assessments, and on neither, which served as the referent group. We then modeled the risk of each learning limitation associated with a top quartile concentration of each protein, and with high and lower concentrations of multiple proteins.
Results: The protein profile of low reading scores was confined to the third and fourth postnatal weeks when increased risks were associated with high concentrations of IL-8 and ICAM-1 in the presence of low concentrations of angio-neurotrophic proteins. The profile of low math scores was very similar, except it did not include ICAM-1. In contrast, the profile of low scores on both assessments was present in each of the first four postnatal weeks. The increased risks associated with high concentrations of TNF-α in the first two weeks and of IL-8 and ICAM-1 in the next two weeks were modulated down by high concentrations of angio-neurotrophic proteins.
Conclusions: High concentrations of angio-neurotrophic proteins appear to reduce/moderate the risk of each learning limitation associated with systemic inflammation. The three categories of limitations have protein profiles with some similarities, and yet some differences, too.
Journal of Child Neurology
Are Extremely Low Gestational Age Newborns Born to Obese Women at Increased Risk of Cerebral Palsy at 2 Years?
Van der Burg, J. W., O’Shea, T. M., Kuban, K. C. K., Allred, E. N., Paneth, N., Dammann, O., Leviton, A.
The authors hypothesized that the risk of cerebral palsy at 2 years in children born extremely preterm to overweight and obese women is increased relative to the risk among children born to neither overweight nor obese women. In a multicenter prospective cohort study, the authors created multinomial logistic regression models of the risk of diparetic, quadriparetic, and hemiparetic cerebral palsy that included the prepregnancy body mass index of mothers of 1014 children born extremely preterm, cerebral palsy diagnoses of children at 2 years, as well as information about potential confounders. Overweight and obese women were not at increased risk of giving birth to a child who had cerebral palsy. The risk ratios associated with overweight varied between 1.1 for quadriparesis (95% CI = 0.5, 2.1) to 2.0 for hemiparesis (95% CI = 0.4, 9.8). The risk ratios associated with obesity varied between 0.7 for diparesis (95% CI = 0.2, 2.5) to 2.5 for hemiparesis (95% CI = 0.4, 13).
Postnatal systemic inflammation and neuro-ophthalmologic dysfunctions in extremely low gestational age children.
Holm, M., Austeng, D., Fichorova, R. N., Allred, E. N., Kuban, K. C. K., O’Shea, T. M., Dammann, O., Leviton, A., ELGAN Study Investigators
AIM: Compared to infants born at term, children born very preterm are at increased risk of visual dysfunctions and neonatal systemic inflammation. Here, we explore whether these two propensities are related.
METHODS: As part of the ELGAN study, the concentrations of 16 mediators of inflammation were measured in blood obtained on postnatal days 1, 7, 14, 21 and 28 from 1062 children born before the 28th week of gestation. Presence of visual field deficit, strabismus and/or impaired visual fixation was recorded at age two. The concentrations of each protein were divided into quartiles within gestational week categories. We calculated odds ratios with 99% confidence intervals for having each disorder comparing children with concentration in the top quartile of each protein to children whose concentration was in the lower quartiles on the corresponding day. Analyses were adjusted for gestational age and birth weight Z-score.
RESULTS: Only one of 80 assessments (16 proteins on five different days) was significant for visual field deficit, and one for impaired fixation. No association was found between strabismus and any inflammatory mediator.
CONCLUSION: None of the three neuro-ophthalmologic dysfunctions assessed at two years appears to be associated with systemic inflammation measured the first four postnatal weeks.
Clinica Chimica Acta
Antecedents and early correlates of high and low concentrations of angiogenic proteins in extremely preterm newborns.
Leviton, A., Ryan, S., Allred, E. N., Fichorova, R. N., O’Shea, T. M., Kuban, K., Dammann, O.,. ELGAN Study Investigators
Background: To identify the antecedents and very early correlates of low concentrations of angiogenic proteins in the blood of extremely preterm newborns during the first postnatal month.
Methods: Using multiplex immunoassays we measured the concentrations of vascular endothelial growth factor A (VEGF), VEGF receptor-1 (VEGFR-1), VEGF receptor-2 (VEGFR-2), placenta growth factor (PIGF), and angiopoietins 1 and 2 (Ang-1, Ang-2), as well as 21 other proteins in blood spots collected on postnatal days 1 (N = 1062), 7 (N = 1087), 14 (N = 989), 21 (N = 940) and 28 (N = 880) from infants born before the 28th week of gestation. We then sought the protein-concentration correlates of concentrations in the top and bottom quartile for gestational age and day the specimen was collected.
Results: Children who were delivered for medical indications and those who were severely growth restricted were more likely than others to have low day-1 blood concentrations of VEGF, VEGF-R2, Ang-1, and PIGF. Systemic inflammation accompanied top quartile concentrations of every one of the 6 angiogenic proteins.
Conclusions: Low day-1 concentrations of most angiogenic proteins are associated with disorders linked to placenta insufficiency/dysfunction. High concentrations, on the other hand, are associated with systemic inflammation throughout the first postnatal month.
Antecedents and correlates of blood concentrations of neurotrophic growth factors in very preterm newborns.
Leviton, A., Allred, E. N., Yamamoto, H., Fichorova, R. N., Kuban, K., O’Shea, T. M., Dammann, O., ELGAN Study Investigators
AIM: To identify the antecedents and very early correlates of low concentrations of neurotrophic growth factors in the blood of extremely preterm newborns during the first postnatal month.
METHODS: Using an immunobead assay, we measured the concentrations of neurotrophin 4 (NT4), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF) in blood spots collected on postnatal days 1 (N=1062), 7 (N=1087), 14 (N=989), 21 (N=940) and 28 (N=880) from infants born before the 28th week of gestation. We then sought the correlates of measurements in the top and bottom quartiles for gestational age and day the specimen was collected.
RESULTS: The concentrations of 2 neurotrophic proteins, NT4 and BDNF, were low among children delivered for medical (maternal or fetal) indications, and among those who were growth restricted. Children who had top quartile concentrations of NT4, BDNF, and bFGF tended to have elevated concentrations of inflammation-related proteins that day. This pattern persisted for much of the first postnatal month.
CONCLUSIONS: Delivery for medical indications and fetal growth restriction are associated with a relative paucity of NT4 and BDNF concentrations during the first 24 h after very preterm birth. Elevated blood concentrations of NT4, BDNF, and bFGF tended to co-occur with indicators of systemic inflammation on the same day.
Early Human Development
Maternal obesity and attention-related symptoms in the preterm offspring.
Van der Burg, J.W., Jensen, E. T., van de Bor, M., Joseph, R. M., O’Shea, T.M., Kubank, K., Allred, E.N., Scott, M., Hunter, S., Hooper, S. R., Dammann, O., Leviton, A.
BACKGROUND: Maternal pre-pregnancy obesity, in term-born children, is associated with an increased risk of attention problems, however this relationship has not been explored among children born extremely preterm.
AIM: To estimate the risk of attention problems at age 10 years in children born very preterm to overweight (i.e., body mass index (BMI) 25-29 kg/m2) and obese (i.e., BMI ≥ 30 kg/m2) women relative to the risk among children born to women who were neither overweight nor obese (i.e. BMI<25kg/m2).
STUDY DESIGN: Multi-center prospective cohort study.
METHODS: A total of 764 children born before the 28th week of gestation and whose mother's pre-pregnancy height and pre-pregnancy weight were obtained at birth had an IQ ≥ 70 at age 10 years when parents and teachers completed Child Symptom Inventory-4 questionnaires that included items about the presence of ADHD.
RESULTS: Compared to children whose mother's pre-pregnancy weight was in the normal range (BMI < 25 kg/m2), children were at increased risk of parent-identified ADHD behaviors if their mother was overweight (odds ratio (OR) = 1.9; 95% confidence interval (CI): 1.1, 3.3), or obese (OR = 2.3; 95% CI: 1.4, 3.9). They were not at increased risk of teacher-identified ADHD characteristics if their mother was overweight before her pregnancy (OR=1.0; 95% CI: 0.6, 1.8), or obese (OR=1.0; 95% CI: 0.6, 1.6).
CONCLUSION: Maternal overweight and obesity are associated with increased risk of parent-identified ADHD characteristics at 10years of age in children born extremely preterm.
Investigative Ophthalmology & Visual Science
Systemic Inflammation-Associated Proteins and Retinopathy of Prematurity in Infants Born Before the 28th Week of Gestation.
Holm, M., Morken, T. S., Fichorova, R. N., VanderVeen, D. K., Allred, E. N., Dammann, O., Leviton, A., & ELGAN Study Neonatology and Ophthalmology Committees
Purpose: To assess the association between systemic levels of inflammation-associated proteins and severe retinopathy of prematurity (ROP) in extremely preterm infants.
Methods: We collected whole blood on filter paper on postnatal days 1, 7, 14, 21, and 28 from 1205 infants born before the 28th week of gestation, and measured the concentrations of 27 inflammation-associated, angiogenic, and neurotrophic proteins. We calculated odds ratios with 95% confidence intervals for the association between top quartile concentrations of each protein and prethreshold ROP.
Results: During the first three weeks after birth, high concentrations of VEGF-R1, myeloperoxidase (MPO), IL-8, intercellular adhesion molecule (ICAM)-1, matrix metalloproteinase 9, erythropoietin, TNF-α, and basic fibroblast growth factor were associated with an increased risk for prethreshold ROP. On day 28, high levels of serum amyloid A, MPO, IL-6, TNF-α, TNF-R1/-R2, IL-8, and ICAM-1 were associated with an increased risk. Top quartile concentrations of the proinflammatory cytokines TNF-α and IL-6 were associated with increased risks of ROP when levels of neuroprotective proteins and growth factors, including BDNF, insulin-like growth factor 1, IGFBP-1, VEGFR-1 and -2, ANG-1 and PlGF, were not in the top quartile. In contrast, high concentrations of NT-4 and BDNF appeared protective only in infants without elevated inflammatory mediators.
Conclusions: Systemic inflammation during the first postnatal month was associated with an increased risk of prethreshold ROP. Elevated
concentrations of growth factors, angiogenic proteins, and neurotrophins appeared to modulate this risk, and were capable of reducing the risk even in the absence of systemic inflammation.
Journal of Neuroimmune Pharmacology
Systemic Inflammation during the First Postnatal Month and the Risk of Attention Deficit Hyperactivity Disorder Characteristics among 10 year-old Children Born Extremely Preterm.
Allred, E. N., Dammann, O., Fichorova, R. N., Hooper, S. R., Hunter, S. J., Joseph, R. M., Kuban, K., Leviton, A., O’Shea, T. M., Scott, M. N.
Although multiple sources link inflammation with attention difficulties, the only human study that evaluated the relationship between systemic inflammation and attention problems assessed attention at age 2 years. Parent and/or teacher completion of the Childhood Symptom Inventory-4 (CSI-4) provided information about characteristics that screen for attention deficit hyperactive disorder (ADHD) among 793 10-year-old children born before the 28th week of gestation who had an IQ ≥ 70. The concentrations of 27 proteins in blood spots obtained during the first postnatal month were measured. 151 children with ADHD behaviors were identified by parent report, while 128 children were identified by teacher report. Top-quartile concentrations of IL-6R, TNF-α, IL-8, VEGF, VEFG-R1, and VEGF-R2 on multiple days were associated with increased risk of ADHD symptoms as assessed by a teacher. Some of this increased risk was modulated by top-quartile concentrations of IL-6R, RANTES, EPO, NT-4, BDNF, bFGF, IGF-1, PIGF, Ang-1, and Ang-2. Systemic inflammation during the first postnatal month among children born extremely preterm appears to increase the risk of teacher-identified ADHD characteristics, and high concentrations of proteins with neurotrophic properties appear capable of modulating this increased risk.
Journal of Perinatology
Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm.
Logan, J. W., Dammann, O., Allred, E. N., Dammann, C., Beam, K., Joseph, R. M., O’Shea, T. M., Leviton, A., Kuban, K. C. K.
OBJECTIVE: A neonatal illness severity score, The Score for Neonatal Acute Physiology-II (SNAP-II), predicts neurodevelopmental impairments at two years of age among children born extremely preterm. We sought to evaluate to what extent SNAP-II is predictive of cognitive and other neurodevelopmental impairments at 10 years of age.
STUDY DESIGN: In a cohort of 874 children born before 28 weeks of gestation, we prospectively collected clinical, physiologic and laboratory data to calculate SNAP-II for each infant. When the children were 10 years old, examiners who were unaware of the child's medical history assessed neurodevelopmental outcomes, including neurocognitive, gross motor, social and communication functions, diagnosis and treatment of seizures or attention deficit hyperactivity disorder (ADHD), academic achievement, and quality of life. We used logistic regression to adjust for potential confounders.
RESULTS: An undesirably high SNAP-II (⩾30), present in 23% of participants, was associated with an increased risk of cognitive impairment (IQ, executive function, language ability), adverse neurological outcomes (epilepsy, impaired gross motor function), behavioral abnormalities (attention deficit disorder and hyperactivity), social dysfunction (autistic spectrum disorder) and education-related adversities (school achievement and need for educational supports. In analyses that adjusted for potential confounders, Z-scores ⩽-1 on 11 of 18 cognitive outcomes were associated with SNAP-II in the highest category, and 6 of 18 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals ranged from 1.4 (1.01, 2.1) to 2.1 (1.4, 3.1). Similarly, 2 of the 8 social dysfunctions were associated with SNAP-II in the highest category, and 3 of 8 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals were slightly higher for these assessments, ranging from 1.6 (1.1, 2.4) to 2.3 (1.2, 4.6).
CONCLUSION: Among very preterm newborns, physiologic derangements present in the first 12 postnatal hours are associated with dysfunctions in several neurodevelopmental domains at 10 years of age. We are unable to make inferences about causality.
Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns.
Yanni, D., Korzeniewski, S. J., Allred, E. N., Fichorova, R. N., O’Shea, T. M., Kuban, K., Dammann, O., Leviton, A.
Background: Preterm newborns exposed to intrauterine inflammation are at an increased risk of neurodevelopmental disorders. We hypothesized that adverse outcomes are more strongly associated with a combination of antenatal and postnatal inflammation than with either of them alone.
Methods: We defined antenatal inflammation as histologic inflammation in the placenta. We measured the concentrations of seven inflammation-related proteins in blood obtained on postnatal days 1, 7, and 14 from 763 infants born before 28 weeks of gestation. We defined postnatal inflammation as a protein concentration in the highest quartile on at least 2 days. We used logistic regression models to evaluate the contribution of antenatal and postnatal inflammation to the risk of neurodevelopmental disorders.
Results: The risk of white matter damage was increased when placental inflammation was followed by sustained elevation of C-reactive protein or ICAM-1. We found the same for spastic cerebral palsy when placental inflammation was followed by elevation of TNF-α or IL-8. The presence of both placental inflammation and elevated levels of IL-6, TNF-α, or ICAM-1 was associated with an increased risk for microcephaly.
Conclusion: Compared with a single hit, two inflammatory hits are associated with stronger risk for abnormal cranial ultrasound, spastic cerebral palsy, and microcephaly at 2 years.
Antecedents of inflammation biomarkers in preterm newborns on days 21 and 28.
Leviton, A., Allred, E. N., Fichorova, R. N., Kuban, K. C. K., O’Shea, T. M., Dammann, O., & ELGAN Study Investigators
AIM: Most studies of systemic inflammation in very preterm newborns focus on assessments made during the first two weeks. The purpose of this study was to identify some of the antecedents of systemic inflammation evident during postnatal weeks three and four.
METHODS: We measured the protein concentrations in blood spots collected on postnatal days 21 (N = 176) and 28 (N = 157) from infants born before the 28th week of gestation and sought correlates of measurements in the top quartile. Odds ratios of elevated concentrations were calculated for the most obvious correlates.
RESULTS: Infants born for maternal and foetal indications were more likely than their peers to have top quartile concentrations of IL-beta, IL-8, TNF-alpha and ICAM-1 on both days 21 and 28. Similarly, infants whose birthweight Z-score was < -2 or between -1 and -2 were also more likely than their peers to have elevated concentrations of these proteins.
CONCLUSION: Markers of systemic inflammation in the very preterm newborn during the third and fourth postnatal weeks are most strongly associated with maternal and foetal indications for (very preterm) delivery and their common correlate/consequence, foetal growth restriction.
Archives of disease in childhood
Fetal and neonatal edition. Systemic endogenous erythropoietin and associated disorders in extremely preterm newborns.
Holm, M., Skranes, J., Dammann, O., Fichorova, R. N., Allred, E. N., Leviton, A.
OBJECTIVE: To explore the association between concentrations of endogenous erythropoietin (EPO) in blood the first 2 weeks of life and neonatal disorders in extremely low gestational age newborns (ELGANs).
DESIGN: Prospective cohort study.
SETTING: Neonatal care units at 14 participating hospitals in the USA.
PATIENTS: 867 children born before the 28th week of gestation from the ELGAN study cohort.
MAIN OUTCOME MEASURES: EPO blood concentrations were measured on postnatal days 1, 7 and 14. The following neonatal characteristics and disorders were registered: blood gases, early and late respiratory dysfunction, pulmonary deterioration, retinopathy of prematurity (ROP), necrotising enterocolitis (NEC) and bronchopulmonary dysplasia (BPD). We calculated the gestational age-adjusted ORs for having each disorder associated with an EPO blood concentration in the highest or lowest quartile, compared with infants whose EPO concentration was in the middle two quartiles on the corresponding day.
RESULTS: Newborns whose day-1 EPO was in the highest quartile were at increased risk for early and persistent respiratory dysfunction during the first 2 weeks of life, and NEC requiring surgery. The lowest EPO quartile on day 1 was associated with a decreased risk of moderate BPD. The association between low EPO and decreased risk of respiratory complications persisted on day 7. On day 14, being in the highest EPO quartile was associated with increased risk of ROP, and BPD not requiring ventilation assistance.
CONCLUSIONS: EPO blood concentrations in extremely preterm newborns during the first 2 weeks of life convey information about increased risks of bowel, lung and retinal diseases.
Antenatal glucocorticoids and neonatal Inflammation-associated proteins.
Faden, M., Holm, M., Allred, E., Fichorova, R., Dammann, O., Leviton, A., ELGAN Study Investigators
Background: To date, studies of the relationship between antenatal glucocorticoids (AGC) and neonatal inflammation in preterm newborns have been largely limited to umbilical cord blood specimens.
Aim: To explore the association between exposure to antenatal glucocorticoids and concentrations of inflammation-related proteins in whole blood collected from very preterm newborns at multiple times during the first postnatal month.
Methods: We measured the protein concentrations on postnatal day 1 (N=1118), day 7 (N=1138), day 14 (N=1030), day 21 (N=936) and day 28 (N=877) from infants born before the 28th week of gestation and explored the relationship between antenatal steroid receipt and protein concentrations in the in the highest and lowest quartiles. The creation of multinomial logistic regression models (adjusted for potential confounders) allowed us calculate odds ratios and 95% confidence intervals.
Results: Twenty of 420 assessments [21 (proteins) × 2 (exposure levels: partial and full) × 2 (quartile levels: top and bottom) × 5 (days)] were statistically significant without any cohesive pattern.
Conclusion: Among infants born before 28 weeks of gestational age, neither full, nor partial courses of antenatal glucocorticoids have a sustained anti-inflammatory effect.
Duration of Systemic Inflammation in the First Postnatal Month Among Infants Born Before the 28th Week of Gestation.
Dammann, O., Allred, E. N., Fichorovy, R. N., Kuban, K. C. K., O’Shea, T. M., Leviton, A., & ELGAN Study Investigators
Extremely low gestational age newborns (ELGANs, <28 completed weeks of gestation) that exhibit fetal and neonatal systemic inflammatory responses are at increased risk for developmental adversity, especially if the inflammatory process is sustained. We evaluated pro-inflammatory cytokine patterns in whole blood of 1220 ELGANs on one or more of postnatal days 1, 7, 14, 21, and 28. Protein concentrations were divided into quartiles within gestational week categories. We calculated odds ratios (OR) with 99 % confidence intervals (CI) for having a concentration in the top quartile for each protein given that the infant had a protein concentration in the top quartile 1 week or more earlier compared to infants who did not. ELGANs who have elevated systemic levels of IL-6R, TNF- α, or RANTES on their first postnatal day are approximately twice as likely to have elevated levels of these cytokines at the end of each of the first postnatal month. In some, this twofold risk increase persisted for the entire first postnatal month. In extremely preterm newborns, inflammatory processes can be sustained over weeks.
Endogenous erythropoietin varies significantly with inflammation-related proteins in extremely premature newborns.
Logan, J. W., Allred, E. N., Fichorova. R. N., Engelke, S., Dammann, O., Leviton, A., & ELGAN Study Investigators
INTRODUCTION: Erythropoietin, a pluripotent glycoprotein essential for erythropoiesis, fetal growth, and development, has recently been implicated in innate immune regulation. Data from the ELGAN Study allowed us to evaluate relationships between endogenous erythropoietin and 25 inflammation-related proteins in extremely premature newborns.
METHODS: We measured the concentrations of 25 inflammation-related proteins and of erythropoietin in blood spots collected on postnatal days 1, 7, and 14 from 936 infants born before 28 weeks gestation. We calculated the odds that infants with an inflammation-related protein in the highest quartile for gestational age and collection day had an erythropoietin concentration in the highest or lowest quartile.
RESULTS: The proportion of children with inflammation-associated protein concentrations in the top quartile tended to increase monotonically with increasing quartile of EPO concentrations on 2 of the 3 days assessed. To a large extent, on each of the 3 days assessed, the odds ratios for an erythropoietin concentration in the top quartile were significantly elevated among those with an inflammation-related protein concentration in the top quartile.
CONCLUSIONS: Our findings suggest that in very preterm newborns, circulating levels of endogenous erythropoietin vary significantly with circulating levels of inflammation-related proteins. Elevation of endogenous erythropoietin might not be an epiphenomenon, but instead might contribute to subsequent events, by either promoting or reducing inflammation, or by promoting an anti-injury or repair capability.
European Journal of Paediatric Neurology
Antecedents and correlates of visual field deficits in children born extremely preterm.
Holm, M., Msall, M. E., Skranes, J., Dammann, O., Allred, E., & Leviton, A.
Aim: We sought to identify the antecedents and correlates of visual field deficits (VFDs) at age 2 years among infants born before the 28th week of gestation.
Methods: The visual fields of 1023 infants were assessed by confrontation at age 2 years. We compared the ante-and postnatal characteristics and exposures of the 65 infants with a VFD to their peers who did not have a VFD. We used time-oriented logistic regression risk models to assess the associations of potential antecedents and correlates with a VFD.
Results: In the final regression model, VFD was associated with maternal consumption of aspirin during the current pregnancy, recurring/persistent acidemia during the first 3 postnatal days, cerebral ventriculomegaly seen on neonatal ultrasound, prethreshold retinopathy of prematurity (ROP), and supplemental oxygen and ventilator dependence at 36 weeks post-menstrual age. Birth before the 27th week was also associated with increased risk, but its significance was diminished by the addition of postnatal variables.
Conclusion: In this sample of extremely preterm born infants, antenatal as well as early and late postnatal characteristics and exposures are associated with an increased risk of having a VFD. Our study adds to our knowledge about the complex etiology of visual deficits of prematurity, and supports a multifactorial cause of these deficits.
Frontiers in System Neuroscience
Systems approach to the study of brain damage in the very preterm newborn.
Leviton, A., Gressens, P., Wolkenhauer, O., Dammann, O.
Background: A systems approach to the study of brain damage in very preterm newborns has been lacking.
Methods: In this perspective piece, we offer encephalopathy of prematurity as an example of the complexity and interrelatedness of brain-damaging molecular processes that can be initiated inflammatory phenomena.
Results: Using three transcription factors, nuclear factor-kappa B (NF-κB), Notch-1, and nuclear factor erythroid 2 related factor 2 (NRF2), we show the inter-connectedness of signaling pathways activated by some antecedents of encephalopathy of prematurity.
Conclusions: We hope that as biomarkers of exposures and processes leading to brain damage in the most immature newborns become more readily available, those who apply a systems approach to the study of neuroscience can be persuaded to study the pathogenesis of brain disorders in the very preterm newborn.
The breadth and type of systemic inflammation and the risk of adverse neurological outcomes in extremely low gestation newborns.
Kuban, K. C. K., O’Shea, T. M., Allred, E. N., Fichorova, R. N., Heeren, T., Paneth, N., Hirtz, D., Dammann, O., Leviton, A., & ELGAN Study Investigators
BACKGROUND: We hypothesized that the risk of brain damage in extremely preterm neonates increases with the breadth and type of systemic inflammation, indexed by the number of elevated inflammation-related proteins and the number of functional categories of inflammation-related proteins exhibiting an elevated concentration.
METHODS: In blood from 881 infants born before 28 weeks gestation, we measured the concentrations of 25 inflammation-related proteins, representing six functional categories (cytokines, chemokines, growth factors, adhesion molecules, metalloproteinases, and liver-produced acute phase reactant proteins) on postnatal days 1, 7, and 14. We evaluated associations between the number and type of proteins whose concentrations were elevated on two separate occasions a week apart and the diagnoses of ventriculomegaly as a neonate, and at 2 years, microcephaly, impaired early cognitive functioning, cerebral palsy, and autism risk as assessed with the Modified Checklist for Autism in Toddlers screen, and in a subset of these children from 12 of 14 sites (n = 826), an attention problem identified with the Child Behavior Checklist.
RESULTS: The risk of abnormal brain structure and function overall was increased among children who had recurrent and/or persistent elevations of the 25 proteins. The risk for most outcomes did not rise until at least four proteins in at least two functional categories were elevated. When we focused our analysis on 10 proteins previously found to be associated consistently with neurological outcomes, we found the risk of low Mental Development Index on the Bayley Scales of Infant Development-II, microcephaly, and a Child Behavior Checklist-defined attention problem increased with higher numbers of these recurrently and/or persistently elevated proteins.
INTERPRETATION: Increasing breadth of early neonatal inflammation, indexed by the number of protein elevations or the number of protein functional classes elevated, is associated with increasing risk of disorders of brain structure and function among infants born extremely preterm.
Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates.
Korzeniewski, S., J., Allred, E., Logan, J. W., Fichorova, R. N., Engelke, S., Kuban, K. C. K., O’Shea, T. M., Paneth, N., Holm, M., Dammann, O., Leviton, A., & ELGAN Study Investigators
Background: We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI).
Methods: Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age.
Results: Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI.
Conclusion: hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.
Journal of Pediatric Endocrinology & Metabolism
Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage?
Korzeniewski, S. J., Soto-Rivera, C. L., Fichorova, R. N., Allred, E. N., Kuban, K. C. K., O’Shea, T. M., Paneth, N., Agus, M., Dammann, O., Leviton, A.
BACKGROUND: We sought to disentangle the contributions of hyperthyrotropinemia (an indicator of thyroid dysfunction) (HTT) and intermittent or sustained systemic inflammation (ISSI) to structural and functional indicators of brain damage.
METHODS: We measured the concentrations of thyroid-stimulating hormone (TSH) on day 14 and of 25 inflammation-related proteins in blood collected during the first 2 postnatal weeks from 786 infants born before the 28th week of gestation who were not considered to have hypothyroidism. We defined hyperthyrotropinemia (HTT) as a TSH concentration in the highest quartile for gestational age on postnatal day 14 and ISSI was defined as a concentration in the top quartile for gestational age of a specific inflammation-related protein on 2 separate days a week apart during the first 2 postnatal weeks. We first assessed the risk of brain damage indicators by comparing 1) neonates who had HTT to those without (regardless of ISSI) and 2) neonates with HTT only, ISSI only, or HTT+ISSI to those who were exposed to neither HTT nor ISSI.
RESULTS: In univariable models that compared those with HTT to those without, HTT was not significantly associated with any indicator of brain damage. In models that compared HTT only, ISSI only, and HTT+ISSI to those with neither, children with ISSI only or with HTT+ISSI were at significantly higher risk of ventriculomegaly [odds ratios (ORs) 2-6], whereas those with HTT only were at significantly reduced risk of a hypoechoic lesion (ORs 0.2-0.4). Children with HTT only had a higher risk of quadriparesis and those with ISSI alone had a higher risk of hemiparesis (ORs 1.6-2.4). Elevated risk of a very low mental development score was associated with both ISSI only and HTT+ISSI, whereas a very low motor development score and microcephaly were associated with HTT+ISSI.
CONCLUSIONS: The association of HTT with increased or decreased risk of indicators of brain damage depends on the presence or absence of ISSI.
Early Human Development
Is maternal obesity associated with sustained inflammation in extremely low gestational age newborns?
Van der Burg, J. W., Allred, E. N., McElrath, T. F., Fichorova, R. N., Kuban, K. C. K., O’Shea, T. M., Dammann, O., & Leviton, A.
BACKGROUND: The offspring of obese women are at increased risk for systemic inflammation. Blood concentrations of inflammatory proteins in preterm newborns of obese women have not been reported.
AIM: To compare blood concentrations in the highest quartile for gestational age of inflammatory proteins and day of blood specimen collection on two days at least one week apart of newborns of overweight (i.e., BMI 25-29) and obese women (i.e., BMI ≥ 30) with newborns of women with lower BMIs. Because deliveries for spontaneous indications are more likely than those for other indications to be associated with inflammation, we evaluated spontaneous indication deliveries separately from maternal or fetal indications.
STUDY DESIGN: Prospective cohort study.
SUBJECTS AND OUTCOME MEASURES: We measured from 939 children born before the 28th week of gestation 25 inflammation-related proteins in blood obtained on postnatal day 1 (range 1-3), day 7 (range 5-8) and day 14 (range 12-15).
RESULTS: Among infants delivered for spontaneous indications, maternal BMI was not related to elevated concentrations of any protein. Among infants delivered for maternal (i.e., preeclampsia) or fetal indications, those whose mother was overweight or obese were more likely than others to have elevated concentrations of inflammation proteins.
CONCLUSIONS: Maternal pre-pregnancy overweight and obesity appear to contribute to a pro-inflammatory state in very preterm newborns delivered for maternal or fetal indications. Our failure to see a similar pattern among newborns delivered for spontaneous indications, which often have inflammatory characteristics, might reflect competing risks.
Risk factors and correlates of neonatal growth velocity in extremely low gestational age newborns: the ELGAN Study.
Bartholomew, J., Martin, C. R., Allred, E., Chen, M. L., Ehrenkranz, R. A. Dammann, O., Leviton, A.
OBJECTIVES: To identify maternal and infant characteristics associated with reduced growth velocity (GV) in extremely premature newborns.
METHODS: We evaluated 1,187 infants born between 23 and 27 weeks' gestation at 14 institutions between 2002 and 2004 who survived until day 28 to identify the maternal and infant characteristics associated with a GV and caloric intake in the lowest quartile.
RESULTS: Newborns in the lowest gestational age and low birth weight categories, as well as those with intrauterine growth restriction, or high SNAP-II received relatively fewer kcal/kg/day than their peers without these risk factors, but were not at increased risk of being in the lowest GV quartile. Newborns with bacteremia, patent ductus arteriosus, retinopathy of prematurity stage 3-5, or pulmonary illness received fewer calories, as did those who received medications or blood transfusions. However, in a multivariable model adjusting for confounders, only ventilator dependence on day 7 (OR 2.2, 95% CI 1.5-3.2), early persistent pulmonary dysfunction (OR 1.8, 95% CI 1.3-2.5), and postnatal exposure to dexamethasone (OR 2.8, 95% CI 1.2-6.5) were associated with an increased risk of being in the lowest GV quartile. In this model, low caloric intake was not associated with low GV (OR 1.3, 95% CI 0.9-1.9).
CONCLUSION: Variables associated with severe pulmonary disease convey more information about the risk of reduced GV during the first 28 postnatal days than does low caloric intake.
Two-hit model of brain damage in the very preterm newborn: small for gestational age and postnatal systemic inflammation.
Leviton, A., Fichorova, R. N., O’Shea, T. M., Kuban, K. C. K., Paneth, N., Dammann, O., Allred, E. N., ELGAN Study Investigators
BACKGROUND: We sought to disentangle the contributions of perinatal systemic inflammation and being small for gestational age (SGA) to the occurrence of low Bayley Mental Development Indices (MDIs) at the age of 2 y.
METHODS: We measured the concentration of 25 inflammation-related proteins in blood obtained during the first two postnatal weeks from 805 infants who were born before the 28th wk of gestation and who had MDI measurements at the age of 2 y and were able to walk independently.
RESULTS: SGA newborns who did not have systemic inflammation (a concentration of an inflammation-related protein in the top quartile for gestational age on two days a week apart) were at a greater risk of an MDI <55, but not 55-69, than their peers who had neither SGA nor systemic inflammation. SGA infants who had elevated blood concentrations of interleukin (IL)-1β, tumor necrosis factor-α, or IL-8 during the first 2 postnatal weeks were at even higher risk of an MDI <55 than their SGA peers without systemic inflammation and their non-SGA peers with systemic inflammation.
CONCLUSION: SGA appears to place very preterm newborns at an increased risk of a very low MDI. Systemic inflammation adds considerably to the increased risk.
Presumed and definite bacteremia in extremely low gestational age newborns.
Patel, S., Dammann, O., Martin, C. R., Allred, E. N., Leviton, A., ELGAN Study Investigators
Aim: To explore risk patterns for presumed and definite, early and late neonatal bacteremia.
Methods: We studied 1106 ELGANs who survived until postnatal day 28. We defined early definite bacteremia as a positive bacterial culture in the first week and definite late bacteremia as a positive bacterial culture in week 2, 3 or 4. Bacteremia was presumed if antibiotics were given for more than 72 hours despite negative blood cultures.
Results: Risk patterns did not differ much for presumed and definite bacteremia in the first postnatal month. While maternal and pregnancy characteristics were associated with early bacteremia, neonatal co-morbidities, especially NEC, were the main antecedents/correlates of late bacteremia. All four categories of bacteremia were associated with younger gestational age and lower birth weight. Infants with presumed and definite bacteremia had similar distributions of days of ventilation and oxygenation.
Conclusion: Definite and presumed late bacteremia have rather similar risk patterns, while those of early and late bacteremia differ appreciably.
Systemic responses of preterm newborns with presumed or documented bacteraemia.
Leviton, A., O’Shea, T. M., Bednarek, F. J., Allred, E. N., Fichorova, R. N., Dammann, O., ELGAN Study Investigators
Aim: To compare the frequency of elevated concentrations of inflammation-related proteins in the blood of infants born before the 28th week of gestation who had documented bacteremia to those who had presumed (antibiotic-treated but culture-negative) bacteremia to those who neither.
Methods: The subjects of this study are the 868 infants born at 14 institutions for whom information about protein measurements on at least two of the three protocol days (days 1, 7, and 14) was available and who did not have Bell stage 3 necrotizing enterocolitis or isolated bowel perforation, which were strongly associated with bacteremia in this sample.
Results: Newborns with presumed early (week 1) bacteremia had elevated concentrations of only a few inflammation-related proteins, while those who had presumed late (weeks 2–4) bacteremia did not have any elevations. In contrast, newborns who had documented early bacteremia had a moderately strong signal, while those who had documented late bacteremia had a stronger signal with more protein concentrations elevated on two separate occasions a week apart.
Conclusions: Culture-confirmed early and late bacteremia are accompanied/followed by systemic inflammatory responses not seen with presumed early and late bacteremia.
Archives of disease in childhood. Fetal and neonatal edition.
Does bronchopulmonary dysplasia contribute to the occurrence of cerebral palsy among infants born before 28 weeks of gestation?
Van Marter, L. J., Kuban, K. C. K., Allred, E., Bose, C., Dammann, O., O’Shea, M., Laughon, M., Ehrenkrank, R. A., Schreiber, M. D., Karna, P., Leviton, A., ELGAN Study Investigators
OBJECTIVE: To evaluate the relationships among cerebral palsy (CP) phenotypes and bronchopulmonary dysplasia (BPD) severity and, in the process, to generate hypotheses regarding causal pathways linking BPD to CP.
STUDY DESIGN: We studied 1047 infants born before the 28th week of gestation. Receipt of supplemental oxygen at 36 weeks postmenstrual age (PMA), with or without the need for mechanical ventilation (MV) at 36 weeks PMA, defined two levels of BPD. At 24 months, the children underwent neurologic examinations and CP diagnoses were made using an algorithm based on topographic localisation.
RESULTS: The 536 infants with BPD were at increased risk of all three CP phenotypes. In time-oriented multivariable analyses that adjusted for potential confounders, receipt of supplemental oxygen without MV at 36 weeks PMA (BPD) was not associated with increased risk of any CP phenotype. In contrast, BPD accompanied by MV at 36 weeks PMA (BPD/MV) was associated with a nearly sixfold increased risk of quadriparesis and a fourfold increased risk of diparesis.
CONCLUSIONS: Combined treatment with both MV and supplemental oxygen at 36 weeks PMA strongly predicts the more common bilateral CP phenotypes. BPD without MV at 36 weeks PMA was not significantly associated with any form of CP.
Archives of Disease in childhood. Fetal and neonatal edition.
Early postnatal hypotension and developmental delay at 24 months of age among extremely low gestational age newborns.
Logan, J. W., O’Shea, T. M., Allred, E. N., Laughon, M. M., Bose, C. L., Dammann, O., Batton, D. G., Engelke, S. C., Leviton, A., & ELGAN Study Investigators
OBJECTIVES: To evaluate in extremely low gestational age newborns, relationships between indicators of hypotension during the first 24 postnatal hours and developmental delay at 24 months of age.
METHODS: The 945 infants in this prospective study were born at <28 weeks, were assessed for three indicators of hypotension in the first 24 postnatal hours, and were evaluated with the Bayley Mental Development Index (MDI) and Psychomotor Development Index (PDI) at 24 months corrected age. Indicators of hypotension included: (1) mean arterial pressure in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile for the difference between the lowest and highest mean arterial pressure. Logistic regression was used to evaluate relationships between hypotension and developmental outcomes, adjusting for potential confounders.
RESULTS: 78% of infants in this cohort received volume expansion or vasopressor; all who received a vasopressor were treated with volume expansion. 26% had an MDI <70 and 32% had a PDI <70. Low MDI and PDI were associated with low gestational age, which in turn, was associated with receipt of vasopressor treatment. Blood pressure in the lowest quartile for gestational age was associated with vasopressor treatment and labile blood pressure. After adjusting for potential confounders, none of the indicators of hypotension were associated with MDI <70 or PDI <70.
CONCLUSIONS: In this large cohort of extremely low gestational age newborns, we found little evidence that early postnatal hypotension indicators are associated with developmental delay at 24 months corrected gestational age.
Blood protein concentrations in the first two postnatal weeks associated with early postnatal blood gas derangements among infants born before the 28th week of gestation. The ELGAN Study.
Leviton, A., Allred, E. N., Kuban, K. C. K., Dammann, O., Fichorova, R. N., O’Shea, T. M., Paneth, N., ELGAN Study Investigators
AIM: To explore the relationships between blood gas derangements and blood concentrations of inflammation-related proteins shortly after preterm birth.
DESIGN: Observational cohort.
SETTING: Fourteen neonatal intensive care units.
SUBJECTS: Seven hundred and forty five infants born before the 28th week of gestation who were classified by their blood gas derangements during the first three postnatal days and by the concentrations of 25 proteins in their blood on days 1, 7, and 14. We classified these newborns by whether or not they had a highest or lowest PaO2, PCO2, and lowest pH in the most extreme quartile, and by whether or not they had a protein concentration in the highest quartile.
RESULTS: Blood gas derangements on two days were much more likely to be accompanied or followed by sustained or recurrent systemic inflammation than a derangement on only one day. This was most evident for acidemia, and slightly less so for hypercapnia.
CONCLUSIONS: Our finding that protein concentration patterns indicative of systemic inflammation are associated with several blood gas derangements raises the possibility that organ damage attributed to these derangements might be accompanied by or involve an inflammatory response.
Journal of Perinatology
Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns.
Logan, J. W., O’Shea, T.M., Allred, E. N., Laughon, M. M., Bose, C. L., Dammann, O., Batton, D. G., Kuban, K. C., Paneth, N., Levtion, A., ELGAN Stuy Investigators
OBJECTIVE: To evaluate, in extremely low gestational age newborns (ELGANs), relationships between indicators of early postnatal hypotension and cranial ultrasound indicators of cerebral white matter damage imaged in the nursery and cerebral palsy diagnoses at 24 months follow-up.
STUDY DESIGN: The 1041 infants in this prospective study were born at <28 weeks gestation, were assessed for three indicators of hypotension in the first 24 postnatal hours, had at least one set of protocol cranial ultrasound scans and were evaluated with a structured neurological exam at 24 months corrected age. Indicators of hypotension included: (1) lowest mean arterial pressure (MAP) in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile of the difference between each infant's lowest and highest MAP. Outcomes included indicators of cerebral white matter damage, that is, moderate/severe ventriculomegaly or an echolucent lesion on cranial ultrasound and cerebral palsy diagnoses at 24 months gestation. Logistic regression was used to evaluate relationships among hypotension indicators and outcomes, adjusting for potential confounders.
RESULT: Twenty-one percent of surviving infants had a lowest blood pressure in the lowest quartile for gestational age, 24% were treated with vasopressors and 24% had labile blood pressure. Among infants with these hypotension indicators, 10% percent developed ventriculomegaly and 7% developed an echolucent lesion. At 24 months follow-up, 6% had developed quadriparesis, 4% diparesis and 2% hemiparesis. After adjusting for confounders, we found no association between indicators of hypotension, and indicators of cerebral white matter damage or a cerebral palsy diagnosis.
CONCLUSION: The absence of an association between indicators of hypotension and cerebral white matter damage and or cerebral palsy suggests that early hypotension may not be important in the pathogenesis of brain injury in ELGANs.
The Journal of Pediatrics
The relationship between early concentrations of 25 blood proteins and cerebral white matter injury in preterm newborns: the ELGAN study.
Leviton, A., Kuban, K. C. K., O’Shea, T. M., Paneth, N., Fichorova, R., Allred, E. N., & Dammann, O.
OBJECTIVE: To evaluate whether concentrations of inflammation-related proteins are elevated in the blood of preterm newborns who develop cerebral white matter damage.
STUDY DESIGN: We measured 25 proteins in blood collected on days 1, 7, and 14 from 939 infants born before the 28th week of gestation. Brain ultrasound scans were read by at least two sonologists, who agreed on the presence or absence of lesions. A protein concentration was considered elevated if it was in the highest quartile for gestational age and the day on which the specimen was collected.
RESULTS: In time-oriented models, elevated concentrations of vascular endothelial growth factor receptor 1, serum amyloid A, and macrophage inflammatory protein 1β on day 1 and interleukin-8 on day 7 were associated with increased risk of ventriculomegaly. Elevated concentrations of macrophage inflammatory protein 1β on day 1 and intercellular adhesion molecule 1 on day 7 were associated with increased risk of an echolucent lesion. Infants with elevated concentrations of inflammation-related proteins on two separate days were at significantly increased risk for ventriculomegaly, but at only modestly increased risk for an echolucent lesion.
CONCLUSIONS: Concentrations of inflammation-related proteins in the circulation in the first days after preterm birth provide information about the risk of sonographic white matter damage. The inflammatory process might begin in utero.
American Journal of Epidemiology
Early blood gas abnormalities and the preterm brain.
Leviton, A., Allred, E., Kuban, K. C. K., Dammann, O., O’Shea, T. M., Hirtz, D., Schreiber, M. D., Paneth, N., & ELGAN Study Investigators
The authors explored associations between blood gas abnormalities in more than 1,000 preterm infants during the first postnatal days and indicators of neonatal brain damage. During 2002-2004, women delivering infants before 28 weeks' gestation at one of 14 participating institutions in 5 US states were asked to enroll in the study. The authors compared infants with blood gas values in the highest or lowest quintile for gestational age and postnatal day (extreme value) on at least 1 of the first 3 postnatal days with the remainder of the subjects, with separate analyses for blood gas abnormalities on multiple days and for partial pressure of oxygen in the alveolar gas of <35. Outcomes analyzed were ventriculomegaly and an echolucent lesion on an ultrasound scan in the neonatal intensive care unit, and cerebral palsy, microcephaly, and a low score on a Bayley Scale of Infant Development at 24 months. Every blood gas derangement (hypoxemia, hyperoxemia, hypocapnia, hypercapnia, and acidosis) was associated with multiple indicators of brain damage. However, for some, the associations were seen with only 1 day of exposure; others were evident with 2 or more days' exposure. Findings suggest that individual blood gas derangements do not increase brain damage risk. Rather, the multiple derangements associated with indicators of brain damage might be indicators of immaturity/vulnerability and illness severity.
Early Human Development
The ELGAN study of the brain and related disorders in extremely low gestational age newborns.
O’Shea, T. M., Allred, E. N., Dammann, O., Hirtz, D., Kuban, K. C. K., Paneth, N., Leviton, A., & ELGAN Study Investigators
BACKGROUND: Extremely low gestational age newborns (ELGANs) are at increased risk for structural and functional brain abnormalities.
AIM: To identify factors that contribute to brain damage in ELGANs.
STUDY DESIGN: Multi-center cohort study.
SUBJECTS: We enrolled 1506 ELGANs born before 28 weeks gestation at 14 sites; 1201 (80%) survived to 2 years corrected age. Information about exposures and characteristics was collected by maternal interview, from chart review, microbiologic and histological examination of placentas, and measurement of proteins in umbilical cord and early postnatal blood spots.
OUTCOME MEASURES: Indicators of white matter damage, i.e. ventriculomegaly and echolucent lesions, on protocol cranial ultrasound scans; head circumference and developmental outcomes at 24 months adjusted age, i.e., cerebral palsy, mental and motor scales of the Bayley Scales of Infant Development, and a screen for autism spectrum disorders.
RESULTS: ELGAN Study publications thus far provide evidence that the following are associated with ultrasongraphically detected white matter damage, cerebral palsy, or both: preterm delivery attributed to preterm labor, prelabor premature rupture of membranes, or cervical insufficiency; recovery of microorganisms in the placenta parenchyma, including species categorized as human skin microflora; histological evidence of placental inflammation; lower gestational age at delivery; greater neonatal illness severity; severe chronic lung disease; neonatal bacteremia; and necrotizing enterocolitis.
CONCLUSIONS: In addition to supporting a potential role for many previously identified antecedents of brain damage in ELGANs, our study is the first to provide strong evidence that brain damage in extremely preterm infants is associated with microorganisms in placenta parenchyma.
Journal of Child Neurology
Cranial ultrasound lesions in the NICU predict cerebral palsy at age 2 years in children born at extremely low gestational age.
Kuban, K. C. K., Allred, E. N., O’Shea, T. M., Paneth, N., Pagano, M., Dammann, O., Leviton, A., Du Plessis, A., Westra, S. J., Miller, C. R., Bassan, H., Krishnamoorthy, K,. Junewick, J., Olomu, N., Romano, E., Seibert, J., Engelke, S., Karna, P., Batton, D., O’Connor, S. E., Keller, C. E., ELGAN Study Investigators
Our prospective cohort study of extremely low gestational age newborns evaluated the association of neonatal head ultrasound abnormalities with cerebral palsy at age 2 years. Cranial ultrasounds in 1053 infants were read with respect to intraventricular hemorrhage, ventriculomegaly, and echolucency, by multiple sonologists. Standardized neurological examinations classified cerebral palsy, and functional impairment was assessed. Forty-four percent with ventriculomegaly and 52% with echolucency developed cerebral palsy. Compared with no ultrasound abnormalities, children with echolucency were 24 times more likely to have quadriparesis and 29 times more likely to have hemiparesis. Children with ventriculomegaly were 17 times more likely to have quadriparesis or hemiparesis. Forty-three percent of children with cerebral palsy had normal head ultrasound. Focal white matter damage (echolucency) and diffuse damage (late ventriculomegaly) are associated with a high probability of cerebral palsy, especially quadriparesis. Nearly half the cerebral palsy identified at 2 years is not preceded by a neonatal brain ultrasound abnormality.
Journal of Child Neurology
Fetal inflammatory response and brain injury in the preterm newborn.
Preterm birth can be caused by intrauterine infection and maternal/fetal inflammatory responses. Maternal inflammation (chorioamnionitis) is often followed by a systemic fetal inflammatory response characterized by elevated levels of proinflammatory cytokines in the fetal circulation. The inflammation signal is likely transmitted across the blood-brain barrier and initiates a neuroinflammatory response. Microglial activation has a central role in this process and triggers excitotoxic, inflammatory, and oxidative damage in the developing brain. Neuroinflammation can persist over a period of time and sensitize the brain to subinjurious insults in early and chronic phases but may offer relative tolerance in the intermediate period through activation of endogenous anti-inflammatory, protective, and repair mechanisms. Neuroinflammatory injury not only destroys what exists but also changes what develops.
Paediatric and Perinatal Epidemiology
Bronchopulmonary dysplasia and brain white matter damage in the preterm infant: a complex relationship.
Gagliardi, L., Bellú, R., Zanini, R., & Dammann, O.
We analysed the relationship between bronchopulmonary dysplasia (BPD) and brain white matter damage (WMD) in very preterm infants, adjusting for common risk factors and confounders. We studied a cohort of infants <32 weeks gestational age (GA) and <1500 g, admitted to 12 hospitals in Northern Italy in 1999–2002. The association between BPD and WMD was estimated by generalised estimating equations and conditional logistic models, adjusting for centre, GA, propensity score for prolonged ventilation and other potential confounders. Directed acyclic graphs (DAG) were used to depict the underlying causal structure and guide analysis.
Of the 1209 infants reaching 36 weeks, 192 (15.8%) developed BPD (supplemental oxygen at 36 weeks) and 88 (7.3%) ultrasound‐defined WMD (cystic periventricular leukomalacia). In crude analysis, BPD was a strong risk factor for WMD [odds ratio (OR) = 5.9]. With successive adjustments, the OR progressively decreased to 3.88 when adjusting for GA, to 2.72 adding perinatal risk factors, and further down to 2.16 [95% confidence interval 1.1, 3.9] when ventilation was also adjusted for. Postnatal factors did not change the OR. Significant risk factors for WMD, in addition to BPD, were a low GA, a lower Apgar score, a higher illness severity score, ventilation and early‐onset sepsis, while antenatal steroids, being small for GA, and surfactant were associated with a reduced risk.
In conclusion, our data suggest that BPD is associated with an increased risk of WMD; most of the effect is due to shared risk factors and causal pathways. DAGs helped clarify the complex confounding of this scenario.
Interinstitutional variation in prediction of death by SNAP-II and SNAPPE-II among extremely preterm infants.
Dammann, O., Shah, B., Naples, M., Bednarek, F., Zupancic, J., Allred, E. N., Leviton, A., ELGAN Study Investigators
BACKGROUND: Illness severity scores predict death among infants admitted to NICUs. We know of no study limited to a population defined by an extremely low gestational age.
METHODS: A total of 1467 infants born before the 28th postmenstrual week at 14 institutions were given Score for Neonatal Acute Physiology II (SNAP-II) and Score for Neonatal Acute Physiology Perinatal Extension II (SNAPPE-II) values based on data collected within the first 12 postnatal hours. All deaths in the intensive care nursery were identified.
RESULTS: The rate of death before postnatal day 28 was 13% (interinstitutional range: 7%-20%), whereas the overall mortality rate was 18% (8%-31%). SNAP-II values, SNAPPE-II values, and mortality rates tended to decrease with increasing gestational age. Even within gestational age strata, however, the risk of death decreased with decreasing SNAP-II and SNAPPE-II values. The positive predictive values of most SNAP-II and SNAPPE-II cutoff levels were close to 30%. In general, institutions' mortality rates increased with the proportions of infants whose SNAP-II values were >/=30.
CONCLUSION: The physiologic instability in the first 12 postnatal hours that is identified by illness severity scores conveys information about the risk of death among infants at the lowest gestational ages.
The Journal of Maternal-Fetal & Neonatal Medicine
Maternal obesity, gestational hypertension, and preterm delivery.
Madan, J., Chen, M., Goodman, E., Davis, J., Allan, W. & Dammann, O.
OBJECTIVE: To study maternal obesity as a risk factor for preterm delivery.
METHODS: Maine State Birth Records Database from 1996 through 2006 was evaluated to investigate obese pregnant women compared with normal weight women regarding risk for preterm delivery. Multiple risk factors and outcomes were studied in univariable and multivariable models.
RESULTS: Among 58,112 pregnant women, 8% (n = 4653) gave birth to preterm infants. Univariable analyses revealed a relationship between obesity and increased risk of prematurity. In multivariable regressions, the most important intermediate variable appears to be gestational hypertension/preeclampsia.
CONCLUSIONS: As maternal body mass index increases in pregnancy, the risk of preterm delivery and other maternal complications increases. The obesity-prematurity relationship is complex, with hypertensive disorders of pregnancy playing a crucial role. More detailed analyses of causal pathways are warranted.
ErbB receptors in fetal endothelium--a potential linkage point for inflammation-associated neonatal disorders.
Bueter, W., Dammann, O., Zscheppang, K., Korenbaum, E.,& Dammann, C. E.
OBJECTIVE: ErbB receptors and their ligands play crucial roles in development. During late gestation, they might also be involved in the pathogenesis of prematurity-associated disorders. ErbB receptor dimerization leads to a diversity of biologic signals. We studied the expression and localization patterns of erbB receptors in the developing human umbilical endothelial cell system. It is still unclear, whether expression patterns might be developmentally regulated and depend on the cell type studied.
METHODS: Primary human umbilical venous endothelial cells (HUVEC) and arterial endothelial cells (HUAEC) were isolated between 24 and 42 weeks of gestation and used for immunoprecipitation, Western blotting, and confocal microscopy.
RESULTS: All four erbB receptors were present in HUVEC and HUAEC. Expression patterns were similar for cell types at gestational ages examined. ErbB4 always co-precipitated with erbB1 in both cell types independent of the gestational age. Confocal microscopy revealed that all erbB receptors were localized in the nucleus, erbB1 and erbB3 in the nucleoli, while erbB2 and erbB4 spared the nucleolar region. All receptors showed a tendency to co-localize. Growth factor stimulation altered localization patterns. Cellular subfractionation experiments for erbB4 largely confirmed microscopy results. Pretreatment with lipopolysaccharide enhanced this nuclear localization of erbB4, particularly of its intracellular domain.
CONCLUSIONS: All erbB receptors are present in both HUVEC and HUAEC at all gestational ages tested. ErbB receptor expression patterns were independent of the developmental stage of the endothelial cell, at least in the third trimester. We speculate that endothelial erbB receptors might play a role in normal development in mid and late gestation. We also speculate that these findings, together with the known involvement of erbB receptors in development, inflammation, and angiogenesis, will open new avenues for erbB receptor-related research in the pathogenesis of fetal and neonatal inflammation-associated disorders.
Journal of Perinatology
Brain lesions in newborns exposed to high-dose magnesium sulfate during preterm labor.
High-dosage, tocolytic magnesium sulfate (MgSO4) administered to pregnant women during preterm labor can be toxic, and sometimes lethal, for their newborns (Cochrane Database of Systematic Reviews (relative mortality risk 2.82, 95% confidence interval 1.2-6.6)). Based on the results of the Magnesium and Neurologic Endpoints Trial and the work of many others, a unifying triangular concept is proposed to account for the increased prevalence of brain lesions, with their likely resultant mortality, in neonates and infants exposed to high-dose MgSO4 in the context of preterm labor. We review the evidence that: (1) elevated circulating levels of serum ionized magnesium occurring in mothers, and therefore in their babies, at the time of delivery are associated with subsequent neonatal intraventricular hemorrhage (IVH); (2) neonatal IVH is strongly associated with lenticulostriate vasculopathy (LSV), an unusual mineralizing lesion involving the thalami and basal ganglia of the neonate; and, (3) exposure to 50 g or more of tocolytic MgSO4 during preterm labor is associated with the development of LSV.
BJOG: An International Journal of Obstretrics and Gynaecology
Lung and brain damage in preterm newborns, and their association with gestational age, prematurity subgroup, infection/inflammation and long term outcome.
Dammann, O., Leviton, A., Gappa, M., & Dammann, C. E. L.
Compared with those born at term, preterm newborns are at an increased risk of short term disorders of the lung (bronchopulmonary dysplasia; BPD) and the brain (white matter damage; WMD), and of long term developmental and pulmonary dysfunctions. Although all of these adverse outcomes are associated with low gestational age, brain, but not lung, damage appears to be associated with the prematurity subgroup [spontaneous preterm labour and/or preterm prelabour rupture of membranes (PPROM) vs pregnancy‐induced hypertension (PIH)]. Part of the association between brain damage and prematurity subgroup might be due to a differential exposure of members of these subgroups to perinatal infection/inflammation. There is a lack of studies evaluating the association of antenatal and perinatal risk factors with late childhood pulmonary dysfunction among those born during the second trimester. In this paper we discuss the complexities that paediatricians, perinatologists and perinatal epidemiologists face as they try to understand the contributions of factors associated with preterm birth to neonatal and childhood disorders.
Developmental Medicine and Child Neurology
Systemic hypotension and white-matter damage in preterm infants.
Dammann, O., Allred, E. N., Kuban, K. C. K., Van Marter, L. J., Pagano, M., Sanocka, U., Leviton, A., & Developmental Epidemioloy Network
This study was designed to test the hypothesis that systemic hypotension during the first postnatal week increases the risk of ultrasonographic echolucency in the white matter of preterm infants (< or = 28 weeks' gestation) while adjusting for confounders. From a study base of 1607 very-low-birthweight neonates (500 to 1500 g), a subsample of 243 preterm infants (122 females; < or = 28 weeks' gestation) was selected for echolucency and data collection prospectively for the entire first postnatal week. Data analyses were performed separately for the first 24 hours of life, for the interval from the end of the first 24 hours to the end of the fourth postnatal day, and for days 5, 6, and 7. Systemic hypotension was defined as the mean arterial blood pressure in the lowest quartile for the infant's week of gestational age. Protocol cranial ultrasounds were those obtained closest to days 1, 7, and 21. A committee of sonologists classified the infants as having either echolucency (echolucency group) or not (control group). Systemic hypotension during the first week of life appeared to be associated with echolucency in univariable analyses but the association did not persist after adjustment for potential confounders. Detailed summaries of 13 previous studies, the majority of which did not show an association between systemic hypotension and white-matter damage, are presented. In sum, these results do not support the hypothesis that systemic hypotension contributes to echolucency among preterm infants.
The Journal of Pediatrics
Association between maternal serum ionized magnesium levels at delivery and neonatal intraventricular hemorrhage.
Mittendorf, R., Dambrosia, J., Dammann, O., Pryde, P. G., Lee, K. S., Ben-Ami, T. E.,Yousefzadeh, D.
OBJECTIVES: To determine whether magnesium sulfate (MgSO(4)) exposure is associated with a reduced risk for neonatal intraventricular hemorrhage (IVH).
STUDY DESIGN: In a randomized, controlled trial, women in preterm labor were randomly assigned to receive MgSO(4), "other" tocolytic, or saline control. At delivery, we collected maternal antecubital and umbilical cord blood for determination of serum ionized magnesium levels. Neonatal IVH was diagnosed by cranial ultrasonogram.
RESULTS: Among 144 infants, 24 were diagnosed with IVH. Using crude intention-to-treat analysis, we found that 18% (13/74) of survivors exposed after birth to MgSO(4) had IVH compared with 16% (11/70) of babies who were not exposed. Infants who had IVH were more likely to have been delivered by mothers with higher serum ionized magnesium (Mg) levels (0.75 vs 0.56 mmol/L) (P =.01). Using multivariable logistic regression, we confirmed that higher Mg levels are a significant predictor of neonatal IVH (adjusted odds ratio, 15.8; 95% CI, 1.4-175.0) even when adjusted for birth weight, gestational age, antenatal hemorrhage, and neonatal glucocorticoid exposure.
CONCLUSIONS: In mothers with preterm labor, our data indicate that antenatal MgSO(4) exposure may be associated with an increased risk for IVH among their newborns.
The Journal of Pediatrics
Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants.
Van Marter, L. J., Dammann, O., Allred, E. N., Leviton, A., Pagano, M., Moore, M., Martin, C., & Developmental Epidemiology Network Investigators
OBJECTIVE: This case-control study of chronic lung disease (CLD) evaluated the hypothesis that chorioamnionitis promotes CLD and interacts with other risk factors for CLD, including mechanical ventilation and postnatal infection.
STUDY DESIGN: We identified a population of 193 infants who met our case criteria for CLD whose birth weights were
RESULTS: Univariable analyses revealed decreased CLD risk associated with histologic chorioamnionitis and increased risk associated with mechanical ventilation >7 days and culture-documented sepsis. In multivariable analyses, infants were at greatest risk for CLD when they had exposure to both chorioamnionitis and either mechanical ventilation >7 days (odds ratio, 3.2; 95% confidence interval, 0.9-11) or postnatal infection (odds ratio, 2.9; 95% confidence interval, 1.1-7.4).
CONCLUSIONS: We conclude that prolonged mechanical ventilation or postnatal infection increases the risk of CLD among surviving preterm infants and that these 2 factors interact with antenatal infection to further increase the risk of CLD.
Support is provided for the hypothesis that activated leukocytes, especially monocytes/macrophages, contribute to cerebral white matter damage in extremely low gestational age newborns. Much of the evidence is indirect and comes from analogies to brain diseases in adults, and from models of brain damage in adult and newborn animals. If the recruitment of circulating cells to the brain contributes to white matter damage in extremely low gestational age newborns, then minimizing the transendothelial migration of circulating cells by pharmacological manipulation might prevent or reduce the occurrence of neonatal white matter damage and the disabilities that follow.
The Journal of Pediatrics
Brain damage in preterm newborns: Biological response modification as a strategy to reduce disabilities.
Substances that promote the growth and maturation of oligodendrocytes and their precursors might protect against white matter injury. We suggest that neuroprotection can also be provided by such modulators of fetal and neonatal inflammatory responses as antiinflammatory cytokines, cytokine-binding proteins, and cytokine-receptor blockers. We briefly describe inflammatory responses in the fetus and newborn and show how they might contribute to brain damage. We conclude with the possibility that so-called biological response modifiers, which are drugs that modulate these inflammatory responses, might reduce the risk of brain damage and disabilities.
Brain damage in preterm newborns: might enhancement of developmentally regulated endogenous protection open a door for prevention?
We present a two-component model of brain white matter damage in preterm neonates. The insult component comprises infection and hypoxia-ischemia, which are both associated with inflammation-related abnormalities in the white matter. The developmental component comprises at least three factors, ie, immaturity of the ependymal/endothelial, oligodendroglial, and endogenous protection systems. All three factors are likely contributors to an increased vulnerability of the preterm newborn's white matter. In this article, we focus on recent developments in oligodendrocyte biology that support the view of certain cytokines and growth factors as oligotrophins based on their capability to enhance oligodendrocyte development or survival. We suggest that research into networks of developmentally regulated endogenous protectors (such as oligotrophins) is necessary to broaden our perspectives in brain injury prevention in preterm newborns.
Seminars in Pediatric Neurology
Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant.
This review synthesizes the literature supporting the hypothesis that infection during or even before pregnancy remote from the fetal brain leads to neonatal white matter damage (NWMD) and its long-term sequelae, including cerebral palsy. First, a framework of five dimensions is presented, including the spectrum of NWMD, its relationship with gestational age, its clinical spectrum, the expressions and correlates of infection, and the mother/child dyad. Second, a summary of the plethora of support for the remote infection/NWMD-hypothesis is presented by drawing on studies published over the past three decades. Although an epidemiological perspective is prominent, we invoke molecular explanations (especially the cytokine hypothesis) for observed associations. Third, the article concludes with a section on future studies needed to characterize and eliminate (pre-) pregnancy infections in the mother and to identify and evaluate potentially neuroprotective strategies in the fetus.
Developmental Medicine and Child Neurology
Does prepregnancy bacterial vaginosis increase a mother's risk of having a preterm infant with cerebral palsy?
In this annotation we discuss the hypothesis that a prenatal (and even preconceptional) maternal infection, bacterial vaginosis increases the risk of intrauterine infection, which in turn increases the risk of newborn white-matter damage, which in turn predicts cerebral palsy among those born preterm, i.e. before 37 completed weeks of gestation. We further hypothesize that early antibioc therapy might not only eradicate this infection but also help prevent both preterm birth and subsequent cerebral palsy. The numbers that begin some of the headings below identify lines (pathways) in the Figure.
Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn.
To evaluate the hypothesis that the proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor-alpha might be the link between prenatal intrauterine infection (IUI) and neonatal brain damage, the authors review the relevant epidemiologic and cytokine literature. Maternal IUI appears to increase the risk of preterm delivery, which in turn is associated with an increased risk of intraventricular hemorrhage, neonatal white matter damage, and subsequent cerebral palsy. IL-1, IL-6, and TNF-alpha have been found associated with IUI, preterm birth, neonatal infections. and neonatal brain damage. Unifying models not only postulate the presence of cytokines in the three relevant maternal/fetal compartments (uterus, fetal circulation, and fetal brain) and the ability of the cytokines to cross boundaries (placenta and blood-brain barrier) between these compartments, but also postulate how proinflammatory cytokines might lead to IVH and neonatal white matter damage during prenatal maternal infection. Interrupting the proinflammatory cytokine cascade might prevent later disability in those born near the end of the second trimester.
European Journal of Endocrinology
Decreasing melatonin and 6-hydroxymelatonin sulfate excretion with advancing gestational age in preterm and term newborn male infants.
Commentz, J. C., Henke, A., Dammann, O., Hellwege, H. H., Willig, R. P.
We investigated the ontogeny of melatonin synthesis during fetal maturation by measuring the melatonin (MLT) and 6-hydroxymelatonin sulfate (MLTS) excretion in the urine of male infants aged 2-7 days and gestational age 26-42 weeks. We found a negative correlation between advancing gestational age and the MLT and MLTS excretion expressed as total 24-h amount, ratio of 24-h amount to creatinine and ratio of 24-h amount to body surface area. The ratio of MLT to MLTS was found to be about ten times higher in the study group than in prepubertal children, which might reflect the immaturity of hepatic sulfation capacities. The total amount of excreted MLT and MLTS was only one-tenth the prepubertal values. No day/night differences in MLT and MLTS excretion could be detected. We conclude that the fetal pineal gland is capable of a limited melatonin synthesis from the 26th week of gestation onwards, with decreasing values reaching its nadir around term. This indicates that the amount of fetal MLT excretion is not determined by synthesizing capacities of the pineal gland but by the development of neural connections to the pineal gland.
An Affiliation of TUFTS UNIVERSITY, School of Public Health and Community Medicine